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The evolutionary dynamics and fitness landscape of clones in our blood

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Somatic mutations acquired in healthy tissues as we age are major determinants of cancer risk. Whether variants confer a fitness advantage or rise to detectable frequencies by chance, however, remains largely unknown. Here, by combining blood sequencing data from ∼50,000 individuals and mathematical models borrowed from statistical physics, we reveal how mutation, genetic drift and fitness differences combine to shape the genetic diversity of healthy blood (‘clonal haematopoiesis’). By analysing the spectrum of variant allele frequencies we quantify fitness advantages for key pathogenic variants and genes and provide bounds on the number of haematopoietic stem cells. Positive selection, not drift, is the major force shaping clonal haematopoiesis. The remarkably wide variation in variant allele frequencies observed across individuals is driven by chance differences in the timing of mutation acquisition combined with differences in the cell-intrinsic fitness effect of variants.

I then go on to describe on-going work in our lab where we exploit serial blood samples (collected from the same individuals each year over decade-long timescales) to watch the genetic evolution that leads to blood cancers and how this differs from the evolution that occurs in cancer-free individuals. We find that some of the key mutations driving blood cancers occur >10 years before cancer diagnosis which opens up the possibility of using these as “bellwethers” for early detection and intervention.

This talk is part of the Biological and Biomedical Physics series.

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